OBJECTIVE: This work aims to investigate the mechanism of Jiawei Danxuan Koukang (JDK) and Quercetin in oral submucous fibrosis (OSF) carcinogenesis. DESIGN: We established an OSF model for rats by injecting Arecoline into the oral mucosa of rats to study the impact of JDK and Quercetin on the progression of OSF and OSCC. Then, the viability, proliferation, and migration ability of Arecoline-induced hOMF, CAL27 and SCC-25 cells in JDK and quercetin intervention were detected. RESULTS: The oral mucosal epithelial cells of OSF model and OSF rats were atrophy and thinning, α-SMA, CollageI, Vimentin, Snail, AR and eukaryotic translation initiation factor 5A2 (eIF5A2) expression increased apparently, and E-cadherin expression decreased. The intervention of JDK and Quercetin reversed the changes in oral mucosal epithelial cells and OSF rats. The levels of AR in CAL27 and SCC-25 cells were higher than those in hOMF cells, and Arecoline intervention increased the levels of AR in hOMF, CAL27 and SCC-25 cells. Overexpression of AR up-regulated eIF5A2 to enhance the viability, proliferation and migration of hOMF, CAL27 and SCC-25 cells, and promoted EMT. Quercetin reversed changes in cell feature, and EMT levels in oe-AR intervention. CONCLUSIONS: JDK and Quercetin inhibited OSF carcinogenesis by inhibiting the AR/eIF5A2 signal-mediated EMT.